New Salicylanilide Derivatives and Their Peptide Conjugates as Anticancer Compounds: Synthesis, Characterization, and Effect on Glioblastoma.

Pharmacologically active salicylanilides (2-hydroxy--phenylbenzamides) have been a promising area of interest in medicinal chemistry-related research for quite some time. This group of compounds has shown a wide spectrum of biological activities, including but not limited to anticancer effects. In this study, substituted salicylanilides were chosen to evaluate the activity on U87 human glioblastoma (GBM) cells.

Targeting the Melanocortin 1 Receptor in Melanoma: Biological Activity of α-MSH-Peptide Conjugates.

Malignant melanoma is one of the most aggressive and resistant tumor types, with high metastatic properties. Because of the lack of suitable chemotherapeutic agents for treatment, the 5-year survival rate of melanoma patients with regional and distant metastases is lower than 10%. Targeted tumor therapy that provides several promising results might be a good option for the treatment of malignant melanomas.

TXNL1 has dual functions as a redox active thioredoxin-like protein as well as an ATP- and redox-independent chaperone.

TXNL1 (also named TRP32, for thioredoxin related protein of 32 kDa) is a cytosolic thioredoxin-fold protein expressed in all cell types and conserved from yeast to mammals, but with yet poorly known function. Here, we expressed and purified human TXNL1 together with several Cys-to-Ser variants, characterizing their enzymatic properties. TXNL1 could reduce disulfides in insulin, cystine and glutathione disulfide (GSSG) in reactions coupled to thioredoxin reductase (TXNRD1, TrxR1) using NADPH, similarly to thioredoxin (TXN, Trx1), but with lower catalytic efficacy due to at least one order of magnitude higher K of TrxR1 for TXNL1 compared to Trx1.

3D cell segregation geometry and dynamics are governed by tissue surface tension regulation.

Tissue morphogenesis and patterning during development involve the segregation of cell types. Segregation is driven by differential tissue surface tensions generated by cell types through controlling cell-cell contact formation by regulating adhesion and actomyosin contractility-based cellular cortical tensions. We use vertebrate tissue cell types and zebrafish germ layer progenitors as in vitro models of 3-dimensional heterotypic segregation and developed a quantitative analysis of their dynamics based on 3D time-lapse microscopy.

Peptide Vaccines in Melanoma: Chemical Approaches towards Improved Immunotherapeutic Efficacy.

Cancer of the skin is by far the most common of all cancers. Although the incidence of melanoma is relatively low among skin cancers, it can account for a high number of skin cancer deaths. Since the start of deeper insight into the mechanisms of melanoma tumorigenesis and their strong interaction with the immune system, the development of new therapeutical strategies has been continuously rising.

Targeting the Gastrin-Releasing Peptide Receptor (GRP-R) in Cancer Therapy: Development of Bombesin-Based Peptide-Drug Conjugates.

Targeted tumour therapy has proved to be an efficient alternative to overcome the limitations of conventional chemotherapy. Among several receptors upregulated in cancer cells, the gastrin-releasing peptide receptor (GRP-R) has recently emerged as a promising target for cancer imaging, diagnosing and treatment due to its overexpression on cancerous tissues such as breast, prostate, pancreatic and small-cell lung cancer. Herein, we report on the in vitro and in vivo selective delivery of the cytotoxic drug daunorubicin to prostate and breast cancer, by targeting GRP-R.

Host cell targeting of novel antimycobacterial 4-aminosalicylic acid derivatives with tuftsin carrier peptides.

Mycobacterium tuberculosis is an intracellular pathogen and the uptake of the antimycobacterial compounds by host cells is limited. Novel antimycobacterials effective against intracellular bacteria are needed. New N-substituted derivatives of 4-aminosalicylic acid have been designed and evaluated.

Novel Assay Platform to Evaluate Intracellular Killing of : and Validation.

One of the main hallmarks of tuberculosis (TB) is the ability of the causative agent to transform into a stage of dormancy and the capability of long persistence in the host phagocytes. It is believed that approximately one-third of the population of the world is latently infected with (), and 5%-10% of these individuals can develop clinical manifestations of active TB even decades after the initial infection. In this latent, intracellular form, the is shielded by an extremely robust cell wall and becomes phenotypically resistant to most antituberculars.

[Application of Asn-Gly-Arg sequence based cyclic peptides for targeted tumor therapy].

The in vivo antitumor effect of two NGR sequence containing peptide-daunomycin conjugates was studied on CD13+ Kaposi's sarcoma s.c. tumor model on SCID mice, and on orthotopically developed CD13- HT-29 colon adenocarcinoma SCID mouse model.

Cellular Internalization and Inhibition Capacity of New Anti-Glioma Peptide Conjugates: Physicochemical Characterization and Evaluation on Various Monolayer- and 3D-Spheroid-Based Platforms.

Most therapeutic agents used for treating brain malignancies face hindered transport through the blood-brain barrier (BBB) and poor tissue penetration. To overcome these problems, we developed peptide conjugates of conventional and experimental anticancer agents. SynB3 cell-penetrating peptide derivatives were applied that can cross the BBB.

Old Polyanionic Drug Suramin Suppresses Detrimental Cytotoxicity of the Host Defense Peptide LL-37.

The host defense peptide LL-37 is the only human cathelicidin, characterized by pleiotropic activity ranging from immunological to anti-neoplastic functions. However, its overexpression has been associated with harmful inflammatory responses and apoptosis. Thus, for the latter cases, the development of strategies aiming to reduce LL-37 toxicity is highly desired as these have the potential to provide a viable solution.

Tailoring Uptake Efficacy of HSV-1 gD Derived Carrier Peptides.

Regions of the virus-1 (HSV-1) glycoprotein D (gD) were chosen to design carrier peptides based on the known tertiary structure of the virus entry receptor complexes. These complexes consist of the following: HSV-1 gD-nectin-1 and HSV-1 gD-herpesvirus entry mediator (HVEM). Three sets of peptides were synthesised with sequences covering the (i) -terminal HVEM- and nectin-1 binding region -5-42, (ii) the 181-216 medium region containing nectin-1 binding sequences and (iii) the -terminal nectin-1 binding region 214-255.

Drug Conjugation Induced Modulation of Structural and Membrane Interaction Features of Cationic Cell-Permeable Peptides.

Cell-penetrating peptides might have great potential for enhancing the therapeutic effect of drug molecules against such dangerous pathogens as (Mtb), which causes a major health problem worldwide. A set of cationic cell-penetration peptides with various hydrophobicity were selected and synthesized as drug carrier of isoniazid (INH), a first-line antibacterial agent against tuberculosis. Molecular interactions between the peptides and their INH-conjugates with cell-membrane-forming lipid layers composed of DPPC and mycolic acid (a characteristic component of Mtb cell wall) were evaluated, using the Langmuir balance technique.

Structure-Activity Relationship of HER2 Receptor Targeting Peptide and Its Derivatives in Targeted Tumor Therapy.

Human epidermal growth factor (HER2) is a transmembrane tyrosine kinase receptor that is frequently overexpressed in breast cancer. Its increased level prognoses a poor patient outcome and a high mortality rate. Despite the widening spectrum of therapies that are becoming available to treat HER2+ breast cancer, its side effects and resistance still make this protein a valuable object of research in targeted tumor therapy.

[Comparison of therapeutic peptides targeting pancreatic cancer].

Despite the small number of cases, pancreatic cancer is one of the biggest challenges in tumor therapy as its treatment is not yet resolved and the expected 5-year survival rate is only 5%. Therefore, innovative solutions for pancreatic cancer are of great importance. Targeted tumor therapy might provide new possibilities in this field.

[Optimization of peptide-drug conjugates for targeted tumor therapy].

In case of cancers with high mortality rate and lacking efficient medication there is a huge need of new, innovative treatments. Targeted tumor therapy, a real breakthrough in this field, is based on the concept that the antitumor agent is linked to a targeting molecule (e.g.

In Vivo Tumor Growth Inhibition and Antiangiogenic Effect of Cyclic NGR Peptide-Daunorubicin Conjugates Developed for Targeted Drug Delivery.

Among various homing devices, peptides containing the NGR tripeptide sequence represent a promising approach to selectively recognize CD13 receptor isoforms on the surface of tumor cells. They have been successfully used for the delivery of various chemotherapeutic drugs to tumor vessels. Here, we report on the murine plasma stability, in vitro and in vivo antitumor activity of our recently described bioconjugates containing daunorubicin as payload.

Matrigel patterning reflects multicellular contractility.

Non-muscle myosin II (NMII)-induced multicellular contractility is essential for development, maintenance and remodeling of tissue morphologies. Dysregulation of the cytoskeleton can lead to birth defects or enable cancer progression. We demonstrate that the Matrigel patterning assay, widely used to characterize endothelial cells, is a highly sensitive tool to evaluate cell contractility within a soft extracellular matrix (ECM) environment.

A Convenient Synthetic Method to Improve Immunogenicity of Related T-Cell Epitope Peptides.

Epitopes from different proteins expressed by (, , ) were selected based on previously reported antigenic properties. Relatively short linear T-cell epitope peptides generally have unordered structure, limited immunogenicity, and low stability. Therefore, they rely on proper formulation and on the addition of adjuvants.

Sequence modification of heptapeptide selected by phage display as homing device for HT-29 colon cancer cells to improve the anti-tumour activity of drug delivery systems.

Development of peptide-based conjugates for targeted tumour therapy is a current research topic providing new possibilities in cancer treatment. In this study, VHLGYAT heptapeptide selected by phage display technique for HT-29 human colon cancer was investigated as homing peptide for drug delivery. Daunomycin was conjugated to the N-terminus of the peptide directly or through Cathepsin B cleavable spacers.

Rewiring of RSK-PDZ Interactome by Linear Motif Phosphorylation.

Phosphorylation of short linear peptide motifs is a widespread process for the dynamic regulation of protein-protein interactions. However, the global impact of phosphorylation events on the protein-protein interactome is rarely addressed. The disordered C-terminal tail of ribosomal S6 kinase 1 (RSK1) binds to PDZ domain-containing scaffold proteins, and it harbors a phosphorylatable PDZ-binding motif (PBM) responsive to epidermal growth factor stimulation.

Enhanced In Vitro Antitumor Activity of GnRH-III-Daunorubicin Bioconjugates Influenced by Sequence Modification.

Receptors for gonadotropin releasing hormone (GnRH) are highly expressed in various human cancers including breast, ovarian, endometrial, prostate and colorectal cancer. Ligands like human GnRH-I or the sea lamprey analogue GnRH-III represent a promising approach for the development of efficient drug delivery systems for targeted tumor therapy. Here, we report on the synthesis and cytostatic effect of 14 oxime bond-linked daunorubicin GnRH-III conjugates containing a variety of unnatural amino acids within the peptide sequence.

Comparative cell biological study of in vitro antitumor and antimetastatic activity on melanoma cells of GnRH-III-containing conjugates modified with short-chain fatty acids.

Peptide hormone-based targeted tumor therapy is an approved strategy to selectively block the tumor growth and spreading. The gonadotropin-releasing hormone receptors (GnRH-R) overexpressed on different tumors (e.g.

Non-blocking modulation contributes to sodium channel inhibition by a covalently attached photoreactive riluzole analog.

Sodium channel inhibitor drugs decrease pathological hyperactivity in various diseases including pain syndromes, myotonia, arrhythmias, nerve injuries and epilepsies. Inhibiting pathological but not physiological activity, however, is a major challenge in drug development. Sodium channel inhibitors exert their effects by a dual action: they obstruct ion flow ("block"), and they alter the energetics of channel opening and closing ("modulation").

Synthesis and in vitro biochemical evaluation of oxime bond-linked daunorubicin-GnRH-III conjugates developed for targeted drug delivery.

Gonadotropin releasing hormone-III (GnRH-III), a native isoform of the human GnRH isolated from sea lamprey, specifically binds to GnRH receptors on cancer cells enabling its application as targeting moieties for anticancer drugs. Recently, we reported on the identification of a novel daunorubicin-GnRH-III conjugate (GnRH-III-[Lys(Bu), Lys(Dau=Aoa)] with efficient in vitro and in vivo antitumor activity. To get a deeper insight into the mechanism of action of our lead compound, the cellular uptake was followed by confocal laser scanning microscopy.